Data gathered in the previous period of this project (MH65737) continue to indicate that activity of locus coeruleus (LC) neurons, the major noradrenergic cell-body group of the brain, is reduced by all effective antidepressant (AD) treatments. This conclusion is now supported by both clinical and basic research. Proposed in this renewal application are studies to examine how this reduction in LC activity may alter what is envisioned to be the "effecter arm" of the neural circuit to thereby lead to amelioration of depressive symptoms. The work proposed here arises from the idea that AD-induced decreased LC activity will result in an increase in the activity of dopaminergic (DA) neurons to produce therapeutic effects. Thus, we propose to advance to that next level of the hypothesized cascade of neural events by measuring electrophysiological activity of DA neurons in the ventral tegmental area (VTA), the cell-body origin of the mesocorticolimbic system, to determine whether their activity is increased by effective AD treatments. Using single-unit electrophysiological recording techniques, the experiments proposed for the next period of this project will examine the effects of a range of AD treatments on activity of VTA-DA neurons. Treatments to be tested are those that we have tested for effects on LC neurons, which include chronic administration of two tricyclics, four selective serotonin reuptake inhibitors, one monoamine oxidase inhibitor, three atypical AD drugs, and also electroconvulsive shock. Under Specific Aim i, using an animal model that has been found to respond to all AD effective treatments tested thus far, we will examine effects on activity of VTA-DA neurons identified electrophysiologically. We show pilot data indicating that firing of VTA-DA neurons is decreased in animals of this model, as is hypothesized to occur in depression. Thus, Specific Aim i determines if AD treatments will counteract the decreased VTA-DA activity associated with depression. Under Specific Aim 2, we then will test effects of three drugs, each drug across a series of doses and also at the same series of doses as used within Aim i, but in Aim 2 these studies will be done on normal, "naive" rats. Aim 2 thus makes possible comparison of dose-response effects obtained in an animal model of depression (Aim i) with those in "normal" rats;this is done to determine how "depression" shifts (elevates?) the therapeutic dose of an AD drug that is required for effect. Finally, under Specific Aim 3, we will investigate the time course for the onset of effects of AD drugs in both LC and VTA-DA neurons, which is suspected to be related to the well-known phenomenon of delayed onset for the therapeutic effectiveness of these drugs. In summary, this project builds on previous findings for LC by progressing to the next step of studying the effects on the midbrain DA system, an area long implicated in depression but, in terms of electrophysiological study, relatively little studied to date.